1. Field of the Invention:
This invention relates to anticancer compositions. More specifically, the invention relates to certain novel heteroarotinoids and derivatives thereof.
2. Description of the Prior Art:
Retinoids (vitamin A and derivatives thereof) constitute a group of compounds of enormous current interest. The stimulus for this interest arises from observations that these compounds exhibit some antitumor activity and exert a preventive activity in models of chemical carcinogensis. Unfortunately, the use of natural retinoids in cancer chemotherapy has some disadvantages. With the exception of trans-retinoic acid, natural retinoids are stored in the liver, and blood levels of the materials do not increase proportionately even after massive doses. Thus, it is difficult to achieve a good distribution and to deliver a retinoid to specific target sites. In addition, acute toxicity has been associated with high dosages of natural retinoids. This "hypervitaminosis A" limits clinical use of such compounds. Modifications of the basic retinoid structure have been the subject of intensive effort recently.
For example, systems with fused aryl rings have shown good potency in a tracheal assay. Such systems have been referred to as arotinoids and several papers on the subject have been published, such as in the European Journal of Medicinal Chemistry, 1980, Vol. 15, pages 9-15, entitled "Arotinoids, A New Class of Highly Active Retinoids" by P. Loeliger, W. Bollag and H. Mayer. Synthesis and stereochemistry are discussed. A second more recent publication has peripherally related derivatives and is entitled "Fluorinated Retinoic Acids and Their Analogues". Synthesis and Biological Activity of Aromatic 6-Fluoro Analogues" by A. J. Lovey and B. A. Pawson. The article appeared in the Journal of Medicinal Chemistry, Vol. 25, pages 71-75 (1982). A review of the entire area of biological activity of retinoids and related compounds has been published in the Journal of Medicinal Chemistry, Vol. 25, pages 1269-1277 (1982). The title is "Retinoids at the Threshold: Their Biological Significance and Therapeutic Potential", by B. A. Pawson, C. W. Ehmann, L. M. Itri, and M. I. Sherman. The first paper contains work which is the most closely related to the compounds cited in this application in terms of preparation from ketones and conversion to the final product through a type of Wittig reaction. However, very few publications involving a heteroatom in the ring systems can be currently found and it is felt that the presence of the heteroatom makes a significant difference in the properties of the heteroarotinoids as compared to the arotinoids.
According to the existing literature, some derivatives of the arotinoids have been found to posses useful biological activities. One type of test for therapeutic potency is the antipapilloma test (cited in the first article above) and the tracheal organ culture assay which is described in an article in the Journal of Cancer Research, Vol. 40,3413-3425 (1980) by D. L. Newton, W. R. Henderson, and M. B. Sporn. The assays assess the ability of the test compound to prevent skin papillomas and carcinomas in mice or to prevent keratinization of cultured tracheal cells which frequently occurs when cells become premalignant. Further evidence on these points can be found in articles entitled "Chemoprevention of Cancer with Retinoids" by M. B. Sporn and D. L. Newton, published in the Federation Processings, Vol. 38, pages 2528-2534 (1979) and "Structure-Activity Relationships of Retinoids in Hamster Tracheal organ Culture" by D. L. Newton, W. R. Henderson, and M. B. Sporn, published in Cancer Research, Vol. 40, pages 3414-3425 1980). Another test for potential anticancer activity of retinoic acid derivatives has been the ornithine decarboxylase assay which has been reviewed recently in connection with an evaluation of some aromatic retinoic acid compounds. The article is entitled "Aromatic Retinoic Acid Analogues. Synthesis and Pharmacological Activity" by M. I. Dawson, R. Chan, P. D. Hobbs, W. Chao, and L. J. Schiff and was published in the Journal of Medicinal Chemistry, Vol. 26, pages 1282-1293 (1983). The compounds of the present inventions were assayed using the tracheal organ culture procedure as well as assayed for the induction of differentiation of human (HL-60) promyelocytic cells.
In an article by Waugh et al. "Synthesis and Characterization of Selected Heteroarotinoids", Journal of Medicinal Chemistry, 1985, 28, 116, a series of heteroarotinoids based on the E isomer of 2-arylsubstituted parapecopenylbenyoates having a 4.4-dimethyl chromanyl-6-yl (or corresponding thiochromanyl or -1-oxothiochromanyl) bicyclic heteroatom containing ring structure as the substituent, the tracheal organ culture assay of selected heteroretinoids are compared with trans-retinoic acid for ability to reverse keratinization in vitamin A deficient hamsters. In an article by Dawson et al. "Conformationally Restricted Retinoids", Journal of Medicinal Chemistry, 1984, 27, 1516, a series of conformationally restricted retinoids was synthesized and acreened in two assays, Keratinization in tracheal organ culture (TOC) from vitamin A deficient hamsters and the inhibition of the induction of mouse epidermal ornithine decarboxylase (ODC) by a tumor promoter. It was found that the toxicity of these compounds correlated with their activity in the TOC assay and that the heterocyclic analogues tended to be less toxic.